Composition for use in the treatment of psychic depression



United States Patent O 3,336,195 COMPOSITION FOR USE IN THE TREATMENT OF PSYCHIC DEPRESSION Donald N. McGregor, Syracuse, N .Y., assignor to Bristol- Myers Company, New York, N.Y., a corporation of Delaware No Drawing. Filed July 6, 1964, Ser. No. 380,663 '1 Claim. (Cl. 167-65) This invention relates to a process for treatment of mental depression and more particularly to the use of N- acetonyl-N-benzyl-N,N-dimethylammonium salts as active ingredients in a method for treatment of psychic depres- SlOIl.

The therapeutic composition of the present invention comprises a quaternary salt of N-acetonyl-N-benzyl-N,N- dimethylamine as an essential active ingredient in combination with a pharmacologically acceptable anion. The composition of the present invention possesses valuable therapeutic utility as an antidepressant and it is the object of the present invention to provide a novel method of counteracting mental depression and apathy without stimulating motor activity.

The therapeutic ingredient is, in the preferred form of the present invention, a quaternary ammonium salt which can be represented by the following formula:

1 OHs-N-C Hs-C-CHs 6B CH3 X wherein X is a nontoxic anion.

The nontoxic anions which would be pharmaceutically acceptable include the halides (chloride, bromide and iodide), (lower)alkyl sulfates, the alkyl and aryl sulfonates, phosphate, maleate, fumarate, succinate, tartrate, oxalate and citrate and other ones known to the art. By exchange reactions the original variant of X may be replaced with another anion. The salts obtained through the variation of X may in some cases have special advantages due to solubility, ease of crystallization, lack of objectionable taste, etc. but these are all subsidiary to the main physiological action which is independent of the character of X Hence, all variations of X are considered equivalent.

The compound of the present invention may be embodied in any of the known pharmaceutical forms for oral, subcutaneous, intramuscular or intravenous administration. Preferably, the compound is prepared in solid compositions for oral administration in unit dosage form as tablets, capsules, pills, granules or powders. Solutions, emulsions or suspensions of the compound of the present invention may be prepared for oral administration. Sterile suspensions or solutions are required for parenteral use and isotonic preparations may also be desirable for injection use.

The term unit dosage form as used in the specification and claim means a physically distinct entity suitable as a unitary dosage for administration, each unit containing a pre-determined quantity of the compound of the present invention. The quantity of the compound contained in the unit dosage form is directly dependent upon the considerations which are well-known in the art of compounding a pharmaceutically active material for therapeutic use. The characteristics of the active compound, the particular therapeutic effect to be achieved, the route of administration and the mechanism of the action of the material in the host are important considerations in determining the quantity of the active compound included in the unit dosage form. Examples of suitable oral unit dosage forms are capsules, pills, tablets, cachets and powder packets 3,336,195 Patented Aug. 15, 1967 for solid compositions, and teaspoonfuls, dropperiuls, ampoules and vials for liquid oral dosage forms.

The tablets or pills can be laminated or otherwise compounded to provide for time-release action of the active compound. For example, the tablet or pill can comprise an inner portion constituting one unit dose and an outer portion constituting another unit dose, the outer portion being in the form of an envelope encompassing the inner portion. The two portions can be separated by an enteric layer which serves to delay the release of the active compound contained in the inner portion by resisting disintegration in the stomach thereby allowing it to pass intact into the intestine where the enteric layer is destroyed releasing the active compound in the inner portion. Such an enteric layer may consist of any number of known substances such as polymeric acids or mixtures thereof, cellulose acetate, cetyl alcohol, shellac and the like.

Examples of oral liquid dosage forms include aqueous solutions and aqueous or oil suspensions and emulsions wherein the product is dissolved or dispersed in a pharmaceutically acceptable carrier or vehicle. Flavoring agents may be added to increase the palatability of the dosage form. Examples of vehicles are cottonseed oil, sesame oil, peanut oil and the like and acceptable dispersing agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, dextran, methyl cellulose and the like.

In the preferred embodiment of this invention, N- acetony1-N-benzyl-N,N-dimethylammonium chloride was mixed with conventional tableting ingredients such as corn starch, lactose, sucrose, stearic acid, sor-bitol, talc and functionally similar materials acceptable as pharmaceutical carriers and binders. The solid unit dosage form would contain the active compound in an amount of at least 10 mg. and would be administered at a time rate designed to achieve the desired pharmacological result.

The unit dosage forms containing the compound of the present invention can include other pharmacologically active compounds such as sedatives, including phenobarbital, barbital and like barbiturates, vitamins, hormones, hypotensive and ataractic agents.

The therapeutic utility of the compound of the present invention for the treatment of depression of the central nervous system was demonstrated in mice. N-acetonyl-N- benzyl-N,N-dimethylammonium chloride administered to mice at doses as low as 50 mgm./kg. p.o. prior to treatment with 5 mgm./kg. reserpine prevented the usual sedative eifect of reserpine. An oral dosage of 2000 mgm./ kg. proved lethal to fifty percent of the mice. When mice are pretreated with monoamine oxidase inhibitors before reserpine dosage, the mice exhibit great motor stimulation. Treatment with the compound of the present invention is advantageous in that it exhibits marked antidepressant activity without the motor stimulation of the usual monoamine oxidase inhibitors.

The following method may be used to prepare the compound of this invention:

Chloro-Z-propanone (8.05 ml., 0.10 mole) was added dropwise to an ice-cooled solution of benzyldimethylamine (13.5 g., 0.10 mole) in 50 ml. of acetonitrile and the mixture was stored for 64 hours at 25 C. The reaction mixture was then poured into 140 ml. of ether and cooled to 5 C. A dark red oil separated and this oil was isolated by decantation and dried under vacuum. Trituration of this oil with acetone resulted in partial crystallization. Seed crystals were removed and the remaining crystals and red oil were dissolved in ml. of acetone. The solution was allowed to cool to 25 C. and the seed crystals were added. The mixture was then cooled to 5 C. and kept for two days. The crystals were then removed by filtration, washed with acetone and dried. Recrystallization was done from ethanol-acetone with a solution of approximately 5 ml. of ethanol with 100 ml. of acetone, the crystals were removed by filtration, washed with acetone and dried yielding 5.15 g. of N-acetonyl-N- benzyl-N,N-dimethylammonium chloride.

AnaIysis.-Calculated for C H NOCl: C, 63.3; H, 7.97; N, 6.16. Found: C, 63.75; H, 7.77; N, 6.47.

What I claim is:

A pharmaceutical composition in unit dosage form for use in the treatment of psychic depression in animals said composition including a pharmaceutical carrier and at 10 least 10 mg. of a compound of the formula 3 3 CHzNCHrC-CH wherein X is a pharmaceutically acceptable nontoxic anion.

References Cited UNITED STATES PATENTS 2,605,286 1/1951 Melamed 260567.6

OTHER REFERENCES Renshaw, C. A.: vol. 24, p. 2199 (1930).

ALBERT T. MEYERS, Primary Examiner.

S. ROSEN, JULIAN S. LEVITI', Examiners.

S. J. FRIEDMAN, Assistant Examiner. 

